Parkinson's disease (PD) is a major public health problem in the world, with an estimated 1,000,000 individuals affected in the United States alone. It is a chronic, progressive, neurodegenerative disease caused by the death of neurons that produce dopamine—dopaminergic neurons—a neurotransmitter essential for proper muscle coordination, movement, and balance in the substantia nigra (SN) of the midbrain. PD symptoms vary from person to person, but the most evident symptoms include resting tremors, rigidity, slow movement, instability, stiffness, problems walking, and reduced facial expression. Other symptoms include mild to severe cognitive dysfunction and mood disorders such as depression and apathy, difficulty sleeping, loss of the sense of smell, constipation, difficulty speaking and swallowing, low blood pressure, and drooling.
Available therapies aim at replacing dopamine in the brain to restore motor function with drugs such L-Dopa. However, chronic pharmacological treatment with the dopamine precursor L-Dopa leads to a display of involuntary abnormal movements called dyskinesias in PD patients and often cognitive impairment. And there is no treatment that prevents deterioration attributable to progressive neurodegeneration. Other approaches involve infusing a protein molecule into the brain but off target effects occur that are unacceptable rendering therapeutic interventions that block or slow down the ongoing degenerative process less than successful.
Currently, no therapies exist that provide either protection or restoration of neuronal function for adult onset neurodegenerative diseases such as PD. Many clinical efforts to provide such benefits by infusion of neurotrophic factors have failed, in spite of robust effects in preclinical assessments. One important reason for these failures is the difficulty, due to diffusion limits, of providing these protein molecules in sufficient amounts to the intended cellular targets in the central nervous system. A great need exists for the development of a novel therapeutic approach that promotes an axonal regenerative response, where axons are able to regrow, reach their targets, and restore function. Gene therapy for the central nervous system is a promising approach to treat Parkinson's Disease (PD) and other central nervous system diseases, including but not limited to Alzheimer's Disease (AD) and Huntington's Disease (HD). This challenge suggests an alternative approach, that of viral construct transduction, to directly activate the intracellular signaling pathways that mediate neurotrophic effects.